[Adeno-associated virus-mediated hepatocyte-specific NDUFA13 overexpression protects against CCl 4 -induced liver fibrosis in mice by inhibiting hepatic NLRP3 activation].

OBJECTIVE: To investigate the protective effect of NDUFA13 protein against acute liver injury and liver fibrosis in mice and explore the possible mechanisms.

METHODS: BALB/C mice (7 to 8 weeks old) were divided into normal group, CCl4 group, CCl4 +AAV-NC group and CCl4 +AAV-NDU13 group ( n =18). Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 twice a week for 3, 5 or 7 weeks, and the recombinant virus AAV8-TBG-NC or AAV8-TBG-NDUFA13 was injected via the tail vein 7-10 days prior to CCl4 injection. After the treatments, pathological changes in the liver of the mice were observed using HE and Masson staining. Hepatic expression levels of NDUFA13 and α-SMA were detected with Western blotting, and the coexpression of NDUFA13 and NLRP3, TNF-α and IL-1β, and α-SMA and collagen Ⅲ was analyzed with immunofluorescence assay.

RESULTS: HE and Masson staining showed deranged liver architecture, necrotic hepatocytes and obvious inflammatory infiltration and collagen fiber deposition in mice with CCl4 injection ( P < 0.001). NDUFA13 expression markedly decreased in CCl4 -treated mice ( P < 0.001), while a significant reduction in inflammatory aggregation and fibrosis was observed in mice with AAV-mediated NDUFA13 overexpression ( P < 0.001). In CCl4 +AAV-NDU13 group, immunofluorescence assay revealed markedly weakened activation of NLRP3 inflammasomes ( P < 0.001), significantly decreased TNF-α and IL-1β secretion ( P < 0.001), and inhibited hepatic stellate cell activation ( P < 0.05) and collagen formation in the liver ( P < 0.001).

CONCLUSION: Mitochondrial NDUFA13 overexpression in hepatocytes protects against CCl4 - induced liver fibrosis in mice by inhibiting activation of NLRP3 signaling.